Category Archives: Tubulin

Background Oxidative stress is supposed to increase lipid accumulation by stimulation of hepatic lipogenesis at transcriptional level. (GSH -71 Glutathione-deficient rats had lower triglyceride concentrations in their livers than the control rats (-23%) whereas the circulating triglycerides and the cholesterol concentrations in plasma and liver were not different between the two groups of rats. Livers of glutathione-deficient rats had lower mRNA abundance of sterol regulatory element-binding protein (SREBP)-1c (-47%) Spot (S)14 (-29%) and diacylglycerol acyltransferase 2 (DGAT-2 -27 and a lower enzyme activity of fatty acid synthase (FAS -26 than livers of the control rats. Glutathione-deficient rats had also a lower hepatic activity of the redox-sensitive protein-tyrosine phosphatase (PTP)1B and a higher concentration of irreversible oxidized PTP1B than control rats. No differences were observed in protein expression of total PTP1B and the mature mRNA encoding active XBP1s a key regulator of unfolded protein and ER stress response. Conclusion This study shows that glutathione deficiency lowers hepatic triglyceride concentrations via influencing lipogenesis. The reduced activity of PTP1B and the higher concentration of irreversible oxidized PTP1B could be at least in part responsible for this effect. Background nonalcoholic fatty liver disease (NAFLD) affects approximately 20-30% of the population in developed countries and is a common finding in patients with metabolic syndrome [1 2 Besides enhanced lipolysis and decreased β-oxidation NAFLD is supposed to be caused also by stimulated lipogenesis [3]. Sterol regulatory element-binding protein (SREBP)-1c is a key transcription factor in controlling the mRNA expression of genes which determine lipogenesis [4]. Since oxidative stress Rabbit polyclonal to ITM2C. is generally participating in the development and progression of diabetes and its complications [5-7] it was assumed that triglyceride accumulation in the liver might be at least in part induced by oxidative stress [8]. Actually recent findings showed that human hepatoma HepG2 cells which were treated with H2O2 accumulated triglycerides through up-regulation of genes encoding SREBP-1c and other genes involved in fatty acid metabolism [8] and experiments from our research group revealed a MK-5108 higher mRNA expression of fatty acid synthase (FAS) glucose-6-phosphate dehydrogenase (G6PDH) and stearoyl-CoA desaturase (SCD)-1 in HepG2 cells treated with pro-oxidant CuSO4 compared MK-5108 to untreated cells [9]. Data from both studies indicate oxidative stress as a stimulator of lipid synthesis in liver. However in contrast to these findings low levels of glutathione induced by administration of buthionine sulfoximine (BSO) a specific inhibitor of γ-glutamylcysteine MK-5108 synthetase [10] have been shown to attenuate ethanol-induced steatosis as well as hepatic triglyceride concentrations in untreated rats [11]. Glutathione is the most abundant thiol antioxidant in mammalian cells that is directly involved in defense of reactive oxygen species and that functions as a cofactor of antioxidant enzymes such as the glutathione peroxidase MK-5108 (GPx) [12]. Although pro-oxidants and many pathological conditions such as inflammatory liver diseases diabetes and hyperglycemia are accompanied by reduced intracellular levels of glutathione [13-15] the effect of inhibited glutathione synthesis as a model for endogenously produced oxidative stress on lipogenesis is not yet well understood. This study investigated the effect of glutathione depletion on lipid concentrations in plasma and liver on expression of genes and activities of enzymes involved in lipid synthesis. Glutathione levels were reduced by administration of BSO. Treatment of animals with BSO has the advantage to lower tissue glutathione levels without any overt toxicity [16] or any effect on the hepatic microsomal and cytosolic enzymes [16 17 Lipid synthesis was investigated at the transcriptional level by the analysis of the mRNA expression of SREBP-1c the key transcription factor involved in the stimulation of lipogenesis in the liver [18 19 and of related enzymes involved in lipid synthesis and at the activity level by analysis of lipogenic enzymes FAS and G6PDH. We assume that protein-tyrosine phosphatase (PTP)1B could play a crucial role in the effect of glutathione depletion on lipid metabolism because PTP1B is a.

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Choice splicing generates protein isoforms that are or differentially portrayed in particular tissue conditionally. the fast kinetics of potassium stations. This choice splicing shift is normally noticed at high regularity in tissue examples from Alzheimer’s disease sufferers recommending that RNA polymerase III cogenes could be upstream determinants of choice splicing that considerably donate to homeostasis and pathogenesis in the brain. Intro The potassium channel-interacting protein (KCNIP4 also known as KChIP4; NCBI Protein database accession no. “type”:”entrez-protein” attrs :”text”:”NP_079497.2″ term_id :”24586671″ term_text :”NP_079497.2″NP_079497.2) is a physical interactor of the α subunit of Kv4 a neuronal A-type voltage-dependent potassium channel (Kitagawa et al. 2007 From the means of such an connection it participates in the rules of the A-type current needed for the generation of slow repeated firing in neurons therefore strongly contributing to the molecular properties of potassium channels (Etcheberrigaray et al. 1993 Shibata et al. 2003 Rhodes et al. 2004 Earlier work shown that KCNIP4 also interacts in vivo and in HEK293 cells with presenilins (PSs) the key LY294002 components of the γ-secretase complex that processes the amyloid precursor protein (APP) to generate the Aβ fragments involved in Alzheimer’s disease (AD; Morohashi et al. 2002 Parks and Curtis 2007 A set of possible GU/RH-II KCNIP4 alternate splicing variants with peculiar biochemical and biophysical properties may account for a complex pattern of splice form-dependent protein-protein relationships (Deng et al. 2005 Pruunsild and Timmusk 2005 With this context the canonical splice variant 1 (also referred to as KChIP41b and hereafter referred to as Var I) is definitely widely expressed in all of the brain cell components tested whereas the on the other hand spliced KCNIP4 variant 4 (also referred to as KChIP4a and hereafter referred to as Var IV; Fig. S1 A and B) is definitely specifically indicated in the globus pallidus and basal forebrain neurons (Baranauskas 2004 Trimmer and Rhodes 2004 Notably these on the other hand spliced cell type-specific KCNIP4 variants also account for changes of the A-type current among different cell types (Patel et al. 2002 Boland et al. 2003 Decher et al. 2004 In fact the fast inactivation of the A-type current physiologically associated with Kv4 channels which takes place when KCNIP4 is definitely canonically spliced to Var I is definitely rapidly transformed inside a slowly inactivated potassium current when an alternative splicing event prospects to the synthesis of KCNIP4 Var IV as a result of reduced trafficking of Kv4 channels to the surface membrane (Holmqvist et al. 2002 Schwenk et LY294002 al. 2008 This condition is definitely associated with an impairment of the electrophysiological properties of the cell influencing the excitatory LY294002 or the inhibitory back-propagating action potentials that ultimately participate in associative events such as long-term potentiation (LTP) and long-term major depression. In addition possible cis- or trans-acting factors that select the alternate splicing forms could travel the cell LY294002 LY294002 to an modified synaptic behavior predicated on the impairment of its excitatory properties. Furthermore the notion a perturbation of LTP might donate to the phenotypic manifestations of neurodegeneration alongside the fact which the other KCNIP4 companions (the PSs) are deeply mixed up in etiology of Advertisement highly suggests a feasible participation of KCNIP4 choice splicing in neurodegenerations. This function hails from our latest identification of a LY294002 couple of 30 RNA polymerase III (PolIII)-reliant noncoding RNAs (ncRNAs) that people proposed as book gene appearance regulatory elements performing by the era of particular PolIII/PolII cogene/gene pairs (Dieci et al. 2007 Pagano et al. 2007 Oddly enough among these transcripts (hereafter known as 38A) maps within KCNIP4 gene intron 1 an area mixed up in choice splicing occasions resulting in Var IV of KCNIP4 (Fig. S1 B) and A. Taking into consideration the antisense settings of 38A regarding KCNIP4 intron 1 we hypothesized that KCNIP4 pre-mRNA and 38A ncRNA might type a feeling/antisense RNA set hence masking KCNIP4.

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